Nouvian, R. M. | bioRxiv Science

bioRxiv2024

Midbrain dopamine D2R regulates the salience of threat-related events

Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine (DA)-neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors (autoD2Rs), but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli. Using Drd2Slc6a3 mice, in which Drd2 is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake. Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally, Drd2Slc6a3 male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing. Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing.

neuroscience↗

bioRxiv2021

Selection of active defensive behaviors relies on extended amygdala dopamine D2 receptors

The ability to efficiently switch from one defensive strategy to another maximizes an animals chance of survival. Here, we demonstrate that the selection of active defensive behaviors requires the coordinated activation of dopamine D2 receptor (D2R) signaling within the central extended amygdala (EA) comprising the nucleus accumbens, the oval bed nucleus stria terminals and the central amygdala. We find that discriminative learning between predictive and non-predictive threat auditory stimuli is unaltered in mice carrying a temporally-controlled deletion of D2R within output neurons of the EA. In contrast, intact EA D2R signaling is required for active avoidance learning and innate flight responses triggered by a visual threat stimulus (looming). Consequently, conditional D2R knockout mice biased defensive responses toward passive defensive strategies. Altogether, these findings identify EA D2R signaling as an important mechanism by which DA regulates the switch from passive to active defensive behaviors, regardless whether of learned or innate threat.

neuroscience↗